The present invention relates to a method of inhibiting matrix metalloproteinases using compounds that are dibenzofuran sulfonamide derivatives. More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
The compounds of the present invention are inhibitors of matrix metalloproteinases, e.g., stromelysin-1 and gelatinase A (72 kDa gelatinase).
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3, and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65).
Stromelysin-1 is also known as MMPO3 and gelatinase A is known as MMP02. In addition, several other matrix metalloproteinases are known:
MMP01xe2x80x94Fibroblast collagenase;
MMP07xe2x80x94Matrilysin;
MMP09Gelatinase B; and
MMP13xe2x80x94Collagenase -3.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing chelating groups has generated potent inhibitors such as peptidehydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation.
The ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-1, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galla Z. S., Sukhova G. K., Lark M. W., and Libby P., xe2x80x9cIncreased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaquesxe2x80x9d, J. Clin. Invest., 1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G., and Humphries S., xe2x80x9cLocalization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization,xe2x80x9d Proc. Nat""l. Acad. Sci., 1991;88:8154-8158).
Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine N. and Powell J. T., xe2x80x9cMetalloproteinases in degenerative aortic diseases,xe2x80x9d Clin. Sci., 1991;81:233-239).
Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee T. H., Hamilton M. A., Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H., and Walden J. A., xe2x80x9cImpact of left ventricular size on the survival in advanced heart failure,xe2x80x9d Am. J. Cardiol., 1993;72:672-676). This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure (Reddy H. K., Tyagi S. C., Tjaha I. E., Voelker D. J., Campbell S. E., and Weber K. T., xe2x80x9cActivated myocardial collagenase in idiopathic dilated cardiomyopathy,xe2x80x9d Clin. Res., 1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D., Tjara I. E., and Weber K. T., xe2x80x9cMyocardial collagenase in failing human heart,xe2x80x9d Clin. Res., 1993;41:681A). Animal models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong P. W., Moe G. W., Howard R. J., Grima E. A., and Cruz T. F., xe2x80x9cStructural remodeling in heart failure: gelatinase induction,xe2x80x9d Can. J. Cardiol., 1994;10:214-220), and cardiac dilation precedes profound deficits in cardiac function (Sabbah H. N., Kono T., Stein P. D., Mancini G. B., and Goldstein S., xe2x80x9cLeft ventricular shape changes during the course of evolving heart failure,xe2x80x9d Am. J. Physiol., 1992;263:H266-H270). Neointimal proliferation, leading to restenosis, frequently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel (Bendeck M. P., Zempo N., Clowes A. W., Galardy R. E., and Reidy M., xe2x80x9cSmooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat,xe2x80x9d Circulation Research, 1994;75:539-545). Northern blotting and zymographic analyses indicated that gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC migration across basement membrane barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSCMs underwent the transition from a quiescent state to a proliferating, motile phenotype (Pauly R. R., Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N., Gluzband Y. A., Smith L., Weinstein C., Lakatta E., and Crow M. T., xe2x80x9cMigration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation,xe2x80x9d Circulation Research, 1994;75:41-54).
Collagenase and stromelysin activities have been demonstrated in fibroblasts isolated from inflamed gingiva (Uitto V. J., Applegren R., and Robinson P. J., xe2x80x9cCollagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva,xe2x80x9d J. Periodontal Res., 1981;16:417-424), and enzyme levels have been correlated to the severity of gum disease (Overall C. M., Wiebkin O. W., and Thonard J. C., xe2x80x9cDemonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva,xe2x80x9d J. Periodontal Res., 1987;22:81-88). Proteolytic degradation of extracellular matrix has been observed in corneal ulceration following alkali burns (Brown S. I., Weller C. A., and Wasserman H. E., xe2x80x9cCollagenolytic activity of alkali burned corneas,xe2x80x9d Arch. Opthalmol., 1969;81:370-373). Thiol-containing peptides inhibit the collagenase isolated from alkali-burned rabbit corneas (Burns F. R., Stack M. S., Gray R. D., and Paterson C. A., Invest. Opththamol., 1989;30:1569-1575).
Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-Hansen H., Parks W. C., Welgus H. G., xe2x80x9cDistinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds,xe2x80x9d J. Clin. Invest., 1994;94:79-88).
Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. Stromelysin-1 may thus prevent the epidermis from healing. Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxamate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing human ovarian carcinoma xenografts. A peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement membrane (Melchiori A., Albili A., Ray J. M., and Stetler-Stevenson W. G., Cancer Res., 1992;52:2353-2356), and the natural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models (DeClerck Y. A., Perez N., Shimada H., Boone T. C., Langley K. E., and Taylor S. M., Cancer Res., 1992;52:701-708). Studies of human cancers have shown that gelatinase A is activated on the invasive tumor cell surface (Strongin A. Y., Marmer B. L., Grant G. A., and Goldberg G. I., J. Biol Chem., 1993;268:14033-14039) and is retained there through interaction with a receptor-like molecule (Monsky W. L., Kelly T., Lin C. -Y., Yeh Y., Stetler-Stevenson W. G., Mueller S. C., and Chen W. -T., Cancer Res., 1993;53:3159-3164). Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P. D., and Giavazzi R., Journal of the National Cancer Institute, 1995;87:293; and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W. G., Santi L., and Albini A., Oncology Research, 1994;6:251-257).
Several investigators have demonstrated consistent elevation of stromelysin and collagenase in synovial fluids from rheumatoid and osteoarthritis patients as compared to controls (Walakovits L. A., Moore V. L., Bhardwaj N., Gallick G. S., and Lark M. W., xe2x80x9cDetection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury,xe2x80x9d Arthritis Rheum., 1992;35:35-42; Zafarullah M., Pelletier J. P., Cloutier J. M., and Marcel-Pelletier J., xe2x80x9cElevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia,xe2x80x9d J. Rheumatol., 1993;20:693-697). TIMP-1 and TIMP-2 prevented the formation of collagen fragments, but not proteoglycan fragments, from the degradation of both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews H. J., Plumpton T. A., Harper G. P., and Cawston T. E., Agents Actions, 1992;37:147-154; Ellis A. J., Curry V. A., Powell E. K., and Cawston T. E., Biochem. Biophys. Res. Commun., 1994;201:94-101).
Gijbels, et al., (J. Clin. Invest., 1994;94:2177-2182) recently described a peptide hydroxamate, GM6001, that suppressed the development or reversed the clinical expression of experimental allergic encephalomyelitis (EAE) in a dose dependent manner, suggesting the use of MMP inhibitors in the treatment of autoimmune inflammatory disorders such as multiple sclerosis. A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T-cells from the blood stream during inflammation (Ramanic A. M. and Madri J. A., xe2x80x9cThe Induction of 72-kD Gelatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent,xe2x80x9d J. Cell Biology, 1994;125:1165-1178). This transmigration past the endothelial cell layer is coordinated with the induction of gelatinase A and is mediated by binding to the vascular cell adhesion molecule-1 (VCAM-1). Once the barrier is compromised, edema and inflammation are produced in the CNS. Leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.
These studies provided the basis for the belief that an inhibitor of stromelysin-1 and/or gelatinase A will treat diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function.
We have identified a series of tricyclic aromatic sulfonamide compounds that are inhibitors of matrix metalloproteinases, particularly stromelysin-1 and gelatinase A, and thus useful as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, comeal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
The present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition comprising administering to the patient a therapeutically effective amount of a compound of Formula I 
wherein M is a natural (L) alpha amino acid derivative having the structure 
X is O, S, S(O)n, CH2, CO, or NRQ;
RQ is hydrogen, C1-C6 alkyl, or xe2x80x94C1-C6 alkyl-phenyl;
R is a side chain of a natural alpha amino acid;
R1 is C1-C5 alkoxy, hydroxy, or xe2x80x94NHOR5;
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
In one embodiment of the invention of Formula I, X is O.
In another embodiment of the invention of Formula I, X is S.
In another embodiment of the invention of Formula I, X is CH2.
In another embodiment of the invention of Formula I, X is NRQ.
In a preferred embodiment of the invention of Formula I, X is O and R2 and R4 are hydrogen.
In another embodiment of the invention of Formula I, X is CO.
In another embodiment of the invention of Formula I, X is S(O)n.
In another preferred embodiment of the invention of Formula I, R1 is hydroxy, C1-C5 alkoxy, xe2x80x94NHOH, or xe2x80x94NHObenzyl.
In still another preferred embodiment, R is the side chain of the natural alpha amino acid glycine, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, or phenylalanine.
In another embodiment, the present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula II 
wherein Z is a natural (L) amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHORc;
Rb is a side chain of a natural alpha amino acid; and
Rc is hydrogen, C1-C5 alkyl, or xe2x80x94CH2 phenyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the method comprising Formula II, the group 
is located at the 2-position of the phenyl ring.
In another preferred embodiment of the method comprising Formula II, the group 
is located at the 3-position of the phenyl ring.
Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula III 
wherein Z is a natural (L) amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHORc;
Rb is a side chain of a natural alpha amino acid; and
Rc is hydrogen, C1-C5 alkyl, or xe2x80x94CH2 phenyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula IV. 
wherein Z is a natural (L) amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHORc;
Rb is a side chain of a natural alpha amino acid; and
Rc is hydrogen, C1-C5 alkyl, or xe2x80x94CH2 phenyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula V 
wherein Z is a natural (L) amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHORc;
Rb is a side chain of a natural alpha amino acid; and
Rc is hydrogen, C1-C5 alkyl, or xe2x80x94CH2 phenyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula VI 
wherein Z is a natural (L) amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHORc;
n is 0 to 2;
Rb is a side chain of a natural alpha amino acid; and
Rc is hydrogen, C1-C5 alkyl, or xe2x80x94CH2 phenyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula VII 
wherein Z is a natural (L) amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHORc;
RQ is hydrogen, C1-C6 alkyl, or C1-C6 alkyl-phenyl;
Rb is a side chain of a natural alpha amino acid; and
Rc is hydrogen, C1-C5 alkyl, or xe2x80x94CH2 phenyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a most preferred embodiment, the compound of Formula I-VIII is:
(L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-acetic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-succinic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxyamide;
(L)-2-(dibenzofuran-2-sulfonylamino)-acetic acid tert-butyl ester;
(L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid tert-butyl ester;
(L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid tert-butyl ester;
(L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid tert-butyl ester;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid tert-butyl ester;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid benzyloxy-amide;
(L)-2-(dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid tert-butyl ester;
(L)-2-(dibenzofuran-3-sulfonylamino)-3-methyl-butyric acid;
3-Methyl-2-(9-methyl-9H-carbazole-3-sulfonylamino)-butyric acid;
2-(9-Benzyl-9H-carbazole-3-sulfonylamino)-3-methyl-butyric acid;
(L)-2-(9H-Fluorene-2-sulfonylamino)-3-methyl-butyric acid;
(L)-2-(5,5-Dioxo-5H-5xcex6-dibenzothiophene-3-sulfonylamino)-3-methyl-butyric acid;
(L)-2-(Dibenzothiophene-2-sulfonylamino)-3-methyl-butyric acid;
(L)-2-(7-Bromo-dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;
(L)-3-Methyl-2-(7-phenyl dibenzofuran-2-sulfonylamino)-butyric acid; and
2-(9H-Carbazole-3-sulfonylamino)-3-methyl-butyric acid.
Also provided by the present invention is a method of treating multiple sclerosis, the method comprising administering to a patient having multiple sclerosis a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating atherosclerotic plaque rupture, the method comprising administering to a patient having an atherosclerotic plaque at risk for rupture a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating aortic aneurism, the method comprising administering to a patient having aortic aneurism a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating heart failure, the method comprising administering to a patient having heart failure a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating periodontal disease, the method comprising administering to a patient having periodontal disease a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating corneal ulceration, the method comprising administering to a patient having corneal ulceration a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating burns, the method comprising administering to a patient having burns a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating decubital ulcers, the method comprising administering to a patient having decubital ulcers a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating chronic ulcers or wounds, the method comprising administering to a patient having chronic ulcers or wounds a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating cancer metastasis, the method comprising administering to a patient having cancer metastasis a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating tumor angiogenesis, the method comprising administering to a patient having tumor angiogenesis a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating arthritis, the method comprising administering to a patient having arthritis a therapeutically effective amount of a compound of Formula I-VIII.
Also provided by the present invention is a method of treating autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes, the method comprising administering to a patient having autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes a therapeutically effective amount of a compound of Formula I-VIII.
The present invention also provides compounds of Formula I 
wherein M is a natural (L) alpha amino acid derivative having the structure 
X is S, S(O)n, CH2, CO, or NRQ;
Rb is a side chain of a natural alpha amino acid;
RQ is hydrogen, C1-C6 alkyl, or xe2x80x94C1-C6 alkyl-phenyl;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHOR5;
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
The present invention also provides compounds of Formula VIII 
wherein M is a natural (L) alpha amino acid derivative having the structure 
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
Rb is a side chain of a natural alpha amino acid;
Ra is C1-C5 alkoxy, hydroxy, or xe2x80x94NHOR5;
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
The present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition comprising administering to the patient a therapeutically effective amount of a compound of Formula I 
wherein M is a natural (L) alpha amino acid derivative having the structure 
X is O, S, S(O)n, CH2, CO, or NRQ;
R is a side chain of a natural alpha amino acid;
R1 is C1-C5 alkoxy, hydroxy, or xe2x80x94NHOR5;
R2 and R4 are independently hydrogen, xe2x80x94C1-C5 alkyl, phenyl xe2x80x94NO2, halogen, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3R5, xe2x80x94CHO, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nNR5R6, xe2x80x94CF3, or xe2x80x94NHCOR5;
each R5 and R6 are independently hydrogen or C1-C5 alkyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term xe2x80x9chalogenxe2x80x9d includes chlorine, fluorine, bromine, and iodine.
The term xe2x80x9cphenylxe2x80x9d also includes substituted phenyl wherein one or more hydrogen on the phenyl ring is replaced with an organic radical. Examples of suitable substituents include, but are not limited to, halogen, C1-C6 alkoxy, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a bond.
The term xe2x80x9cside chain of a natural alpha amino acidxe2x80x9d means the group Q in a natural amino acid of formula H2Nxe2x80x94CH(Q)xe2x80x94COOH. Examples of side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
A natural alpha amino acid is an amino acid found in a living organism. Examples of such amino acids include glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, asparagine, glutamine, lysine, arginine, tryptophan, histidine, cysteine, methionine, aspartic acid, and glutamic acid.
The functional groups in the amino acid side chains can be protected. For example, carboxyl groups can be esterified, amino groups can be converted to amides or carbamates, hydroxyl groups can be converted to ethers or esters, and thiol groups can be converted to thioethers or thioesters.
The compounds of Formula I-VIII can be administered to a patient either alone or as part of a pharmaceutically acceptable composition. The compositions can be administered to patients such as humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg/kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. The term xe2x80x9cpatientxe2x80x9d includes humans and animal.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977:66(1-19) which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, nontoxic esters of the compounds of this invention include C1 to C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5 to C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1 to C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary C1 to C6 alkyl amines, and secondary C1 to C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 to C3 alkyl primary amines and C1 to C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention are administered to a patient in need of matrix metalloproteinase inhibition. In general, patients in need of matrix metalloproteinase inhibition are those patients having a disease or condition in which a matrix metalloproteinase plays a role. Examples of such diseases include, but are not limited to, multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
In a preferred embodiment, the matrix metalloproteinase is stromelysin-1 or gelatinase-A.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount of a compound of Formula I-VIII that when administered to a patient having a disease that can be treated with a compound of Formula I-VIII ameliorates a symptom of the disease. A therapeutically effective amount of a compound of Formula I-VIII is readily determined by one skilled in the art by administering a compound of Formula I-VIII to a patient and observing the results.
The following examples illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the Claims, in any manner.